Very little is known about the catabolism of Abeta in its soluble, oligomeric and fibrillar forms. Limited published work and our own preliminary data in laboratory animals indicate that Abeta peptides, when systemically injected in mice, have a short half-life in the circulation, being the liver the main catabolic organ and the hepatocytes the cells involved in the uptake and degradation. Binding on the cell surface and dose-dependent internalization suggest a receptor-mediated mechanism. In addition, in apoE transgenic animals, Abeta catabolism seems to be differentially influenced by the apoE isoform expressed by the transgenesis. Whether or not similar mechanisms take place in brain cells, these findings prompted various mechanistic questions that are the focus in this proposal. Is there a receptor-mediated Abeta uptake in the brain? Is it dependent on the peptide's structure? Is it restricted to a particular cell type? Is this mechanism age-related? Which is the role of apolipoproteins in the clearance and catabolism of Abeta? We hypothesize that conformational transitions of Abeta (monomeric-oligomeric-fibrillar) greatly affect their catabolism within brain cells, resulting in Abeta accumulation and the concomitant formation of the amyloid deposits seen in AD. We propose to (aim 1) study Abeta catabolism in vivo in the brain of wild-type mice, transgenics for human apoES and apoE4, KOs for apoE and apoJ, inducible KOs for LRP-1, as well as in transgenic animals with well established amyloid lesions (i.e. APPsw) using monomeric/dimeric, oligomeric and fibrillar Abeta species in conjunction with the tyramine-cellobiose cellular trapping technique; and (aim 2) dissect the catabolic mechanism of Abeta monomers/dimers, oligomers and fibrils in brain cells using tissue culture techniques to assess the mode of Abeta surface binding, uptake, and degradation as well as the identity of the putative receptor(s) involved in the Abeta - cell interaction.